Field of the Invention
The present invention relates to a process for the preparation of cyeclopropylamine from .gamma.-butyrolactone (hereinafter identified as "butyrolactone"). More particularly, the invention relates to the stage of a process in which a .gamma.-chlorobutyric acid ester ("chlorobutyric acid ester") is cyclized to a cyclopropanecarboxylic acid ester.
Cyclopropylamine is an important precursor for the synthesis of pharmaceuticals and agricultural chemicals. An inexpensive method of preparing the compound is, therefore, desirable. Cyclopropylamine is usually prepared from .gamma.-butyrolactone via the intermediate stages of .gamma.-chlorobutyric acid ("chlorobutyric acid"), chlorobutyric acid ester, cyclopropanecarboxylic acid ester and cyclopropanecarboxylic acid amide. This reaction sequence and individual intermediate stages have been described in several instances. It is thus known that cyclopropanecarboxylic acid ethyl ester can be prepared by cyclization of chlorobutyric acid ethyl ester with sodium t-amylate as the cyclizing base, the yield being only 45% (Julia et al, Bull. Soc. Chim. France 1960, 306 et seq.). A yield of 66% which was achieved in the preparation of cyclopropanecarboxylic acid ethyl ester by reaction of chlorobutyric acid ethyl ester with sodium methylate (Bunce et al., Organic Preparations and Procedures 6, 193-6 [1969]) is also unsatisfactory.
The five-stage reaction sequence mentioned for the preparation of cyclopropylamine in the form of an aqueous solution is described, for example, in U.S. Pat. No. 3,711,549 or DE 19 39 759. In this process, butyrolactone is first converted with hydrogen chloride into chlorobutyric acid, which is subsequently or simultaneously esterified with a lower alkanol to give the chlorobutyric acid alkyl ester. The ester is then cyclized in the presence of an inert solvent such as toluene, to the cyclopropanecarboxylic acid ester, which then reacts with ammonia in the reaction mixture under base catalysis to give cyclopropanecarboxylic acid amide, which is finally degraded to cyclopropylamine in a Hofmann reaction. In the texts of the patents, only the methylate is mentioned as the chlorobutyric acid ester and only sodium methylate is mentioned as the base for the cyclization. The overall yield of cyclopropylamine, based on chlorobutyric acid ester, is stated as 80%, and the yield in the cyclization step is stated as about 92%. A disadvantage of this process is that lower esters of chlorobutyric acid are more difficult to prepare than the esters of higher alcohols. This difference in ester preparation results from the fact that the water formed during the reaction can be discharged azeotropically from the reaction mixture and separated as a separate phase in the condensate only using higher alcohols. The addition of an inert, water-immiscible solvent for azeotropic removal of water leads to an increased expenditure upon distillation.
The process disclosed in EP 0 043 949, which comprises two intermediate stages, also has a similar disadvantage. In this process, chlorobutyric acid methyl or ethyl ester is cyclized with sodium methylate or potassium methylate in the presence of liquid ammonia in one step to give the cyclopropanecarboxylic acid methyl or ethyl ester. The ester is amidated. The yield of cyclopropanecarboxylic acid amide is indeed &gt;90%. However, liquid ammonia is a substance which requires particular safety precautions when used. Furthermore, metering of liquid ammonia is more expensive in terms of apparatus than metering of ammonia in gaseous form.
According to EP 0 205 403, in a process for the preparation of cyclopropylamine starting from butyrolactone, chlorobutyric acid esters of secondary or tertiary alcohols are cyclized to a sterically hindered cyclopropanecarboxylic acid ester by means of solid sodium hydroxide in an inert solvent with the addition of a phase transfer catalyst. Esters of tertiary alcohols such as tert-butanol, gave the best results. Of the esters of secondary alcohols, the isopropyl and 2-butyl ester were mentioned. The yields are stated as &gt;90%. However, in this case the chlorobutyric acid ester must be purified by distillation, which makes the process expensive, as does the use of phase transfer catalysts such as tributylmethylammonium chloride. Furthermore, the subsequent amidation step requires monosodium ethylene glycolate, which is relatively expensive to prepare. The yield of cyclopropylamine over all the stages is about 80%.
The intermediate stage in which a cyclopropanecarboxylic acid ester is converted into the amide has also already been described in several instances. Thus, according to EP 0 662 470, cyclopropanecarboxylic acid esters of lower alcohols having 1-3 carbon atoms are amidated using an alkali metal alcoholate of a monohydric alcohol having 1-8 carbon atoms as a catalyst. No inert solvent is necessary here to achieve good yields. However, the reaction is performed only up to an ester conversion of 60-90%, so that the reaction mixture can still be handled. After removal of the cyclopropane-carboxylic acid amide, the mother liquor, which still contains cyclopropanecarboxylic acid ester, can be recycled to the amidation reaction, so that the yields of &gt;90% are finally achieved. This process is advantageous only if cyclopropanecarboxylic acid esters of lower alcohols having 1-3 carbon atoms are favorably available.
The process disclosed in EP-B1 0 365 970 also leads from cyclopropanecarboxylic acid ester to cyclopropanecarboxylic acid amide. An ester of a C.sub.4 - to C.sub.8 -alcohol is employed, an alkali metal alcoholate of a C.sub.1 - to C.sub.8 -alcohol is used, and the process is operated with gaseous ammonia. The yields here are &gt;95%. A particularly preferred ester is the isopropyl ester, no information being given as to its preparation. The space/time yield of the process is low, since cyclopropanecarboxylic acid esters of higher alcohols have a relatively high molecular weight, while cyclopropanecarboxylic acid amide has a comparatively low molecular weight.
The Hofmann degradation of cyclopropanecarboxylic acid amide to cyclopropylamine is described in three other patent specifications. On the one hand, the amide can be degraded continuously to the amine in solution either in a temperature range of from 10-35.degree. C. (EP 0 367 010) or of from 45-260.degree. C. (EP 0 393 350). On the other hand, the degradation takes place semi-continuously in suspension if, after prechlorination of the amide, which proceeds at a low temperature, the then homogeneous solution is passed continuously through a tube reactor at elevated temperature (DE 195 23 868.0). In all cases, yields of cyclopropylamine of &gt;90%, based on the amide employed, are obtained. A prerequisite of the processes mentioned is the availability of pure cyclopropanecarboxylic acid amide, which must be prepared by the very expensive routes described above.
In spite of the numerous proposals of synthesis, a need continues to exist for an improved process for the preparation of cyclopropylamine starting from butyrolactone which gives a high overall yield and high space/time yields, operates with readily accessible catalysts and occurs without the presence of inert solvents. In particular, a need continues to exist for an improved cyclization reaction which can be used in the process mentioned and starts from readily available chlorobutyric acid esters.